A new RAGE blocker, low anti‐coagulant 2‐O,3‐O desulfated heparin (ODSH), diminishes smoke‐induced pulmonary inflammation

Abstract

Research performed in our lab has implicated the receptor for advanced glycation end-products (RAGE), a pattern recognition receptor, in pulmonary inflammation induced by tobacco smoke, diesel particulate matter, and hyperoxia. Recent work has also demonstrated that low anti-coagulant 2-O,3-O-desulfated heparin (ODSH) may function as an effective blocker of RAGE-ligand interactions as evidenced by inhibition of RAGE ligation with its disparate ligands including CML-BSA (AGE), HMGB-1, and S100b. The current study sought to characterize the anti-inflammatory effects of ODSH in BALB/c mice exposed to acute tobacco smoke. Mice were anesthetized and administered PBS or cigarette smoke extract (CSE, 0.02 cigarettes per dose) +/− 50 ug ODSH via nasal installation. Bronchoalveolar lavage fluid (BALF) was obtained 48 hours after exposure and analyzed. CSE induced a significant increase in total protein, total leukocyte count, PMN count, and cytokine concentration including TNF-alpha in BALF. ODSH administration resulted in a significant decrease in CSE-induced total protein, PMN quantity, and cytokine concentration in BALF compared to controls. The data show that ODSH blockade of RAGE and parallel signaling mechanisms can diminish smoke-induced pro-inflammatory events. Work was supported by the Flight Attendant¡¦s Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).